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IMMUNE RESPONSES BY GLIA DURING NEUROTROPIC CORONAVIRUS INDUCED
ENCEPHALOMYELITIS
by
Karen Emmerette Malone
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PATHOBIOLOGY)
December 2008
Copyright 2008 Karen Emmerette Malone
Object Description
| Title | Immune responses by glia during neurotropic coronavirus induced encephalomyelitis |
| Author | Malone, Karen Emmerette |
| Author email | kmalone@usc.edu; flutedevil@yahoo.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Pathobiology |
| School | Keck School of Medicine |
| Date defended/completed | 2008-06-16 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-10-22 |
| Advisor (committee chair) | Hofman, Florence |
| Advisor (committee member) |
Hinton, David Gardner, Judy |
| Abstract | The data presented in this thesis is incorporated into the model of early events of coronavirus infection and focuses on the innate responses by glia and their potential interactions with the mounting adaptive immune response. By utilizing transgenic mice to purify distinct populations of glia at different times during coronavirus infection of the central nervous system, the unique cell-specific responses can be evaluated in vivo to provide a fuller picture of the events leading to persistent viral infection. These new findings emphasize the protective role of microglia in providing early IFNalphabeta expression and the indirect modulation of this response by T cell activity. Microglia express a broad repertoire of pathogen associated pattern receptors (i.e. TLRs and RIG-I family helicases) and thereby trigger IFNalphabeta expression in direct response to viral infection. IFNalphabeta expression declines in correlation with effective clearance of virus from microglia by T cell activity. Oligodendroglia upregulated their expression of cytosolic receptors for viral RNA products, RIG-I and Mda5, during infection. However oligodendroglia were incapable of recognizing coronavirus infection and did not induce IFNalphabeta expression.; Reliance on exogenous IFNalphabeta by mature oligodendroglia appears to be a prevailing factor driving the preferential infection of oligodendroglia during the acute phase of infection. IFNy can only partially compensate for the loss of IFNbeta mediated anti-viral protection for infected oligodendroglia. Rather IFNy functions primarily in regulating MHC expression in a cell-specific manner thereby facilitating necessary T cell interactions that are also required for control of viral infection. A combination of factors support the persistent infection of oligodendroglia including their lack of autocrine IFNalphabeta activity as well as their limited response to exogenous IFNalphabeta, and their coordinated expression of the inhibitory ligand PD-L1 with MHC class I in response to IFNy. The contribution of these findings to the current model of coronavirus infection in the central nervous system identifies previously unknown roles for glia and underscores the requirement for an intact innate immune response by resident cells in finally attaining a successful adaptive immune response. |
| Keyword | murine coronavirus; glia; neurosciences; interferon; immunity; major histocompatibility complex; T-cell response; anti-viral response |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m1693 |
| Rights | Malone, Karen Emmerette |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Malone-2110 |
| Archival file | uscthesesreloadpub_Volume40/etd-Malone-2110.pdf |
Description
| Title | Page 1 |
| Full text | IMMUNE RESPONSES BY GLIA DURING NEUROTROPIC CORONAVIRUS INDUCED ENCEPHALOMYELITIS by Karen Emmerette Malone A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (PATHOBIOLOGY) December 2008 Copyright 2008 Karen Emmerette Malone |
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